Method of making a blood gas/electrolyte control

ABSTRACT

Aqueous solutions containing buffers and electrolytes are adjusted to levels required for calibration of both blood gas analyzers and ion selective electrolyte analyzers. A control material, composed of similar matrix, is adjusted to three levels of blood gas and electrolyte conditions. These quality control materials are used to monitor blood gas/electrolyte laboratory instrumentation.

This is a continuation of application Ser. No. 08/252,383, filed Jun. 1,1994, and now U.S. Pat. No. 5,422,278 issued Jun. 6, 1995, which is acontinuation of application Ser. No. 08/004,211, filed Jan. 13, 1993,and now abandoned, which is a continuation of application Ser. No.07/794,693, filed on Nov. 18, 1991, now abandoned which is acontinuation of application Ser. No. 07/628,990, filed on Dec. 17, 1990,now abandoned, which is a continuation of application Ser. No.07/511,824, filed on Apr. 16, 1990, now abandoned, which is acontinuation of application Ser. No. 07/361,836, filed on June 1, 1989,now abandoned, which is a continuation of Ser. No. 07/121,499, filed onNov. 17, 1987, now abandoned.

FIELD OF THE INVENTION

This invention relates to aqueous solutions containing buffers andelectrolytes adjusted to specific levels for calibration or qualitycontrol of chemical analyzers. In particular, this invention relates toa solution which has the specific parameters for the calibration andquality control of both blood gas and ion selective electrodeinstrumentation.

BACKGROUND OF THE INVENTION

Analytical devices capable of determining various parameters in wholeblood with the aid of ion-selective electrodes have been used inintensive care units and in the field of anaesthetics. Blood gases, suchas carbon dioxide and oxygen, can be measured using ion selectiveelectrodes. An ion selective electrode consists of an electrochemicalhalf-cell (an internal electrolyte solution and an internal referenceelectrode) and a sensing membrane. These types of electrodes are used tomeasure one type of ion in the presence of other ions in the bodilyfluids. To obtain accurate measurements, a set of calibration solutionsare used to calibrate the electrodes.

In addition to calibration, the tests run on clinical chemical analyzersare verified by specific control solutions. Under ideal conditions,control materials used in the verification of instrumentationperformance should have essentially the same constituents as thosepresent in the fluid which is to be subjected to analysis.

Most blood gas instruments are currently calibrated using a buffer forthe pH and humidified gases for carbon dioxide and oxygen. Someinstruments tonometer buffer inside the instrument and use this liquidfor equilibration. Blood gas instruments that also measure electrolyteshave separate solutions for calibration and control of the ion selectiveelectrodes. The electrolyte calibrator and control solutions do notcurrently contain all the blood gas parameters.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to calibrating and control solutions forinstrumentation which measures both blood gas and electrolytes and amethod of using such solutions with blood gas instruments. Thisinvention relates to aqueous solutions containing buffers andelectrolytes adjusted to specific levels for calibration or qualitycontrol blood gas instruments. In particular, the present inventionrelates to a novel blood gas-electrolyte instrument control solutionhaving three levels. The three levels simulate three different patientconditions: one normal and two abnormal. Level one has low electrolyteparameters, acidosis pH and gas parameters which represent respiratoryacidosis, i.e. low O₂ and high CO₂ concentrations. Level two has normalconditions in all parameters. Level three has high electrolyteparameters, alkalosis pH, and gas parameters which represent respiratoryalkalosis, i.e. low CO₂ and high O₂ concentrations.

Additionally, the present invention relates to a novel blood gaselectrolyte instrument calibrating solution that contains parametersnecessary for the calibration of both blood gas and ion selectiveelectrode instrumentation. In particular, the present calibratingsolution contains two levels having the necessary parameters. Level onehas normal pH, pCO₂ and pO₂ and electrolytes. Level two is the zerooxygen calibrator. It has physiologically high concentrations of CO₂,physiologically low electrolyte levels and zero O₂.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The blood gas-electrolyte calibrating solutions of this invention areprepared by conventional manufacturing techniques using readilyavailable materials. A typical calibrating solution with thecontemplation of this invention is prepared by simply combining inappropriate relative proportions buffer, electrolytes, and otherstandard auxiliary reagents.

EXAMPLE I

A Diamond Sensor System GEM 6 Blood Gas Electrolyte monitor iscalibrated with a calibrating solution having two levels. Thecalibrating solution is comprised of an aqueous biological buffer with apreservative, electrolytes, and blood gas components. A detergent isadded for use as a wetting agent.

Level one has normal pH, pCO₂, pO₂. Sulfate ions are used to keep thecalcium in solution. Level two is the "O" calibrator. It has low pH,physiologically high concentrations of CO₂ and zero O₂ andphysiologically low electrolyte levels. The O₂ is kept at zero, even inthe presence of room air, with sufficient sulfite and nitrogen.

                  TABLE I                                                         ______________________________________                                                        LEVEL 1 LEVEL 2                                               ______________________________________                                        NaCL (mMol/L)     --        46                                                CaCl.sub.2 (mMol/L)                                                                             3.8       0.3                                               KCL (mMol/L)      6.9       2.2                                               Sulfite (mMol/L)  --        40                                                Sulfate (mMol/L)  26        --                                                CO.sub.2 (mmHg)   35        65                                                O.sub.2 (mmHg)    115-170   0                                                 MOPS (mMol/L)     100       100                                               pH (37° C.)                                                                              7.4       6.9                                               Na.sup.+ (mMol/L) 135       150                                               K.sup.+ (mMol/L)  6.0       2                                                 Ca.sup.2+ (mMol/L)                                                                              2.0       0.2                                               CL.sup.- (mMol/L) 120       80                                                Ionic Strength mMol/L                                                                           160       160                                               ______________________________________                                    

Table I lists the composition of the two levels of the blood gaselectrolyte calibrating solution together with concentrations and pHvalues. The pH of the solution is adjusted and sodium bicarbonate isadded to reach the desired carbon dioxide level. Albumin may be added ifa protein matrix is desired.

The electrolytes used in this control solution may be: sodium,potassium, calicum, and chloride. Lithium is not added to thecalibrating solutions or controls for the DSS GEM 6 instrument due tointerference with the sensors, although, with other instruments lithiummay be used. The buffer used is designed to give the appropriate pHvalue by combining the acid and salt forms. This buffer was selected dueto the very small temperature effect demonstrated by the buffer. Varioussolutions having the above discussed levels can be prepared for as manycalibration points as necessary for the instrumentation. Mostinstrumentation use a one or two point calibration for slopingelectrodes.

The final solution is sterile filtered and is stored in gas tightcontainers without a gaseous headspace. In the final container nofurther equilibrium with gases will take place and the final solution istherefore not affected by pressure and temperature.

The addition of calcium as an electrolyte and bicarbonate as a bufferfor pH and carbon dioxide, creates conditions for the formation ofcalcium carbonate. Calcium carbonate is an insoluble precipitate, whichwill eventually remove all the calcium from solution and therefore makethe calcium no longer measurable as an ion. To prevent this fromoccurring sulfate ions are added which protect the calcium ion fromcontact with the carbonate ion. This protection is necessary when highlevels of both calcium and carbon dioxide are desired.

The level I solution is tonometered with 100% nitrogen until the oxygenlevel is less than 10 mmHg. Sulfite ions are then added to scavenge theremaining oxygen. The sulfite is added in excess so that residualsulfite is available to scavenge oxygen that may contact the solution.This enables the solution to maintain a zero oxygen value. Thebicarbonate is then added to create the desired pCO₂ value.

The solutions are then tonometered using the appropriate gases needed toreach the requested oxygen and carbon dioxide values (the finalsolutions are sterile filtered and stored in gas tight containerswithout headspace). No further equilibrium with gases takes place andthe final solution is not affected by pressure and temperature. Thesolution is stable in the final container and is ready for use with ablood gas/electrolyte analyzer.

EXAMPLE II

The blood gas-electrolyte controls of this invention are prepared byconventional manufacturing techniques using readily available materials.A typical control within the contemplation of this invention is preparedby simply combining in appropriate relative proportions, buffer,electrolytes, foaming agent and other standard auxiliary reagents andchemicals; the pH and concentration of dissolved carbon dioxide thereofbeing adjusted to the appropriate value, depending on the natures, thecontrol, an aliquot thereof placed in a sealable receptacle: thereceptacle flushed with gas: and the receptacle sealed so as to create aheadspace above control fluids which is occupied by the gas. Albumin maybe added if a protein matrix is desired. Glycine is added to bind aportion of the calcium to provide a total calcium value that reflectsnormal values for Level II and abnormal values for Levels I and III. Theglycine also prevents precipitation of the remaining ionized calcium.

The performance of a Diamond Sensor Gem 6 Blood Gas-Electrolyte monitoris verified using a blood gas-electrolyte control. The controls arecomprised of three levels: normal and two abnormal conditions. Levelone, an abnormal control, having low electrolyte levels, acidosis pH andgas levels which represent respiratory, acidosis, level two, normalparameters and level three, high levels of electrolytes, alkalosis pHand gas levels which represent respiratory alkalosis, were formed in thepresence of the biological bufferN-2-hydroxyethylpiperazine-N'-2'ethanesulfonic acid. This buffer wasselected due to the temperature effect demonstrated by the buffer. Thetemperature coefficient (change in pKa per degree C.=0.014), enables thecontrol to indicate a malfunction of the instrument temperatureregulation. The material is packaged in glass ampules which have beenflushed with the appropriate gases. This ampule must be shaken prior touse in a blood gas-electrolyte analyzer. The shaking equilibrates thegas with the liquid and also creates a foam layer. The foam layer willprotect the solution from contamination with room air gases for 4minutes after opening the ampule.

                  TABLE II                                                        ______________________________________                                                    LEVEL 1 LEVEL 2    LEVEL 3                                        ______________________________________                                        NaCL (mMol/L) 41        48         79                                         CaCl.sub.2 (mMol/L)                                                                         2.1       2.9        3.4                                        KCL (mMol/L)  2.5       4.2        6.8                                        Glycine (mMol/L)                                                                            639       599        532                                        O.sub.2 (mmHg)                                                                              40        100        150                                        CO.sub.2 (mmHg)                                                                             60        40         13                                         HEPES (mMol/L)                                                                              50        50         50                                         pH (37° C.)                                                                          7.16      7.4        7.6                                        Na.sup.+ (mMol/L)                                                                           120       138        150                                        K.sup.+ (mMol/L)                                                                            2.5       4          6.8                                        Ca.sup.2+ (mMol/L)                                                                          0.9       1.15       1.5                                        Total Ca (mg/dl)                                                                            8.5       11.5       13.5                                       CL.sup.- (mMol/L)                                                                           86        102        116                                        Ionic Strength mMol/L                                                                       160       160        160                                        ______________________________________                                    

Table II lists the composition of the three levels of the bloodgas-electrolyte control solution together with concentrations and pHvalues.

The calibrator and control solutions are currently used to calibrate andcontrol the Diamond Sensor Systems GEM-6 blood gas electrolyte monitor.The two level calibrator solutions are used to perform two calibrationpoints on the instrumentation. The calibration points at 37 C. are:

    ______________________________________                                                   LOW                                                                PARAMETER* CALIBRATOR    HIGH CALIBRATOR                                      ______________________________________                                        pH         6.9 ± 0.02 7.4 ± 0.02                                        pCO.sub.2  65 mmHg ± 3.0                                                                            35 mmHg ± 3.0                                     pO.sub.2   0 mmHg ± 5.0                                                                             115 ± 5.0                                         K.sup.+    2.0 mM/L ± 0.3                                                                           6.0 mM/L ± 0.3                                    Ca.sup.++  0.2 mM/L ± 0.1                                                                           2.0 mM/L ± 0.1                                    ______________________________________                                         *Stated values are at atmospheric pressure, temperature coefficient of pH     = -.01 pH unit/C.                                                        

EXAMPLE III

The control formulations by typical blood gas electrolyteinstrumentation. Table III shows the results of some of these tests.

                  TABLE III                                                       ______________________________________                                        Typical Values Expected                                                       Aqueous Blood Gas/Electrolyte Control                                                                            Expected                                   Parameter                                                                              Level   Instrument  Mean  Range 1SD                                  ______________________________________                                        pH       I       Il 1303     7.16  7.14-7.28                                                                            0.002                               pH       I       Corning 178 7.17  7.15-7.19                                                                            0.006                               pH       I       NOVA Stat   7.15  7.13-7.17                                                                            0.001                               pH       II      Il 1303     7.39  7.37-7.41                                                                            0.004                               pH       II      Corning 178 7.41  7.39-7.43                                                                            0.002                               pH       II      NOVA Stat   7.40  7.36-7.42                                                                            0.006                               pH       III     Il 1303     7.63  7.62-7.65                                                                            0.002                               pH       III     Corning 178 7.63  7.61-7.65                                                                            0.001                               pH       III     NOVA Stat   7.64  7.62-7.66                                                                            0.003                               pCO.sub.2 mmHg                                                                         I       Il 1303     64    59-69  1.0                                 pCO.sub.2 mmHg                                                                         I       Corning 178 67    62-72  2.8                                 pCO.sub.2 mmHg                                                                         I       NOVA Stat   66    61-71  1.0                                 pCO.sub.2 mmHg                                                                         II      Il 1303     36    32-40  0.2                                 pCO.sub.2 mmHg                                                                         II      Corning 178 36    32-40  0.4                                 pCO.sub.2 mmHg                                                                         II      NOVA Stat   36    32-40  0.8                                 pCO.sub.2 mmHg                                                                         III     Il 1303     11.0   9-13  0.1                                 pCO.sub.2 mmHg                                                                         III     Corning 178 8.0    6-10  0.1                                 pCO.sub.2 mmHg                                                                         III     NOVA Stat   11.0   9-13  0.1                                 pO.sub.2 mmHg                                                                          I       Il 1303     42    34-50  1.4                                 pO.sub.2 mmHg                                                                          I       Corning 178 41    33-49  2.0                                 pO.sub.2 mmHg                                                                          I       NOVA Stat   42    34-50  1.3                                 pO.sub.2 mmHg                                                                          II      Il 1303     104    96-112                                                                              2.0                                 pO.sub.2 mmHg                                                                          II      Corning 178 106    98-114                                                                              3.0                                 pO.sub.2 mmHg                                                                          II      NOVA Stat   102    94-110                                                                              3.9                                 pO.sub.2 mmHg                                                                          III     Il 1303     180   172-188                                                                              2.5                                 pO.sub.2 mmHg                                                                          III     Corning 178 183   175-191                                                                              3.1                                 pO.sub.2 mmHg                                                                          III     NOVA Stat   189   183-199                                                                              2.5                                 Sodium   III     NOVA 6      139   134-144                                                                              0.8                                 mM/L                                                                          Sodium   III     NOVA Stat   141   136-146                                                                              1.0                                 mM/L                                                                          Sodium   III     NOVA 10     144   139-149                                                                              1.0                                 mM/L                                                                          Potassium                                                                              I       NOVA 6      2.4   2.1-2.7                                                                              0.1                                 mM/L                                                                          Potassium                                                                              I       NOVA Stat   2.5   2.2-2.8                                                                              0.1                                 mM/L                                                                          Potassium                                                                              I       NOVA 10     2.4   2.1-2.7                                                                              0.1                                 mM/L                                                                          Potassium                                                                              II      NOVA 6      4.0   3.7-4.3                                                                              0.1                                 mM/L                                                                          Potassium                                                                              II      NOVA Stat   3.8   3.5-4.1                                                                              0.1                                 mM/L                                                                          Potassium                                                                              II      NOVA 10     3.8   3.5-4.1                                                                              0.1                                 mM/L                                                                          Potassium                                                                              III     NOVA 6      6.4   6.1-6.7                                                                              0.1                                 mM/L                                                                          Potassium                                                                              III     NOVA Stat   6.9   6.6-7.2                                                                              0.1                                 mM/L                                                                          Potassium                                                                              III     NOVA 10     0.65  6.2-6.8                                                                              0.1                                 mM/L                                                                          iCa mM/L I       NOVA 6      0.8   0.6-1.0                                                                              0.1                                 iCa mM/L I       NOVA Stat   0.8   0.6-1.0                                                                              0.1                                 iCa mM/L II      NOVA 6      1.1   0.9-1.3                                                                              0.1                                 iCa mM/L II      NOVA Stat   1.1   0.9-1.3                                                                              0.1                                 iCa mM/L III     NOVA 6      1.6   1.4-1.8                                                                              0.1                                 iCa mM/L III     NOVA Stat   1.6   1.4-1.8                                                                              0.1                                 Chloride I       NOVA Stat   96    93-99  0.4                                 mM/L                                                                          Chloride I       NOVA 10     96    93-99  0.2                                 mM/L                                                                          Chloride II      NOVA Stat   108   104-112                                                                              1.0                                 mM/L                                                                          Chloride II      NOVA 10     108   104-112                                                                              0.1                                 mM/L                                                                          Chloride III     NOVA Stat   124   120-128                                                                              0.3                                 mM/L                                                                          Chloride III     NOVA 10     124   121-129                                                                              0.1                                 mM/L                                                                          Total Ca I       NOVA 10     0.9   0.7-1.1                                                                              0.2                                 mg/L                                                                          Total Ca II      NOVA 10     1.0   0.8-2.2                                                                              0.2                                 mg/L                                                                          Total Ca III     NOVA 10     1.8   1.6-2.0                                                                              0.2                                 mg/L                                                                          Lithium  I       Corning Flame                                                                             0.6   0.4-0.8                                                                              0.3                                 mM/L                                                                          Lithium  II      Corning Flame                                                                             1.7   1.5-1.1                                                                              0.3                                 mM/L                                                                          Lithium  III     Corning Flame                                                                             3.0   2.8-3.2                                                                              0.3                                 mM/L                                                                          ______________________________________                                    

While these calibrating and control systems are particularlyadvantageous in biological fluid analysis systems such as Diamond SensorSystems GEM-6 it will be apparent that other biological fluid analysissystems can use the presently described calibrating and controlsolutions. Therefore, while particular embodiments of the invention havebeen shown and described, various modifications will be apparent tothose skilled in the art and therefore is not intended that theinvention be limited to the disclosed embodiments or to details thereofand departures may be made there from within the spirit and scope of theinvention.

What is claimed is:
 1. A method of making a control for use with ablood-gas-electrolyte chemical analyzer, the method comprising:(a)employing an aqueous solution of electrolytes comprising sodium ions,potassium ions, calcium ions, and chloride ions; (b) controlling thelevel of gaseous oxygen in said aqueous solution to maintain a pO₂ from40 to 200 mmHg; (c) adding bicarbonate ions to said aqueous solution toprovide CO₂ ; (d) adding a buffering system to said aqueous solution toprovide a pH of between about 6.9 and 7.8; and (e) adding a stabilizerfor calcium ions to said aqueous solution in order to prevent theprecipitation of calcium ions as calcium carbonate.
 2. The method ofclaim 1 wherein the stabilizer for calcium ions is selected from thegroup consisting of sulfate ions and glycine.
 3. The method of claim 2wherein the electrolytes in said aqueous solution further compriselithium ions.
 4. The method of claim 2 wherein the buffering systemcomprises a temperature sensitive buffer.
 5. The method of claim 4wherein the temperature sensitive buffer is selected from the group ofbuffers consisting of N-2-hydroxyethylpiperazine-N'2-ethanesulfonic acidand 3-(N-morpholino) propane sulfonic acid.
 6. The method of claim 2wherein the aqueous solution is stored in a gas tight container.
 7. Themethod of claim 6 wherein the aqueous solution further comprises afoaming agent wherein the concentration of the foaming agent issufficient to form a foam layer when the solution is shaken and providesan open container stability up to approximately four minutes.
 8. Themethod of claim 7 wherein aliquots of the aqueous solution are preparedwith different levels of the electrolytes, gaseous oxygen andbicarbonate ion and each aliquot is stored in a separate gas tightcontainer.